癫痫患儿血白细胞介素-1β、可溶性白细胞介素-2受体和肿瘤坏死因子-α含量的研究

目的：探讨癫痫的免疫学发病机制。方法：选择原发性全身型癫痫呈强直和（或）阵挛发作患儿６０例为研究对象，分为服用苯巴比妥、卡马西平及未服药３组，测定其外周血单核细胞（ＰＢＭＣ）在植物血凝素（ＰＨＡ）的作用下释放白细胞介素１β（ＩＬ１β）、肿瘤坏死因子α（ＴＮＦα）的量及血清ＴＮＦα、可溶性白细胞介素２受体（ＳＩＬ２Ｒ）的含量，并与对照组比较。结果：３组癫痫患儿间各指标含量均无显著性差异（Ｐ均＞０．０５），但均明显高于对照组（Ｐ＜０．０５～０．００１）。结论：癫痫患儿ＰＢＭＣ释放ＩＬ１β、ＴＮＦα的量及血清ＳＩＬ２Ｒ、ＴＮＦα含量的明显增高可能是由于细胞免疫异常等所致，其增高的幅度与是否进行抗癫痫治疗、药物种类及病程长短无关     

癫痫产生及发展过程中γ-氨基丁酸A受体突触后的改变

近年来对惊厥活动中γ-氨基丁酸A受体的细胞、药理、遗传学方面的研究显示抑制性γ-氨基丁酸A受体的结构和功能的改变与癫痫发生和癫痫持续状态密切相关。尤其是γ-氨基丁酸A受体亚单位的基因突变与原发性全面性癫痫发作有着密切的联系。     

白细胞介素1β、白细胞介素1受体拮抗剂对癫痫大鼠行为、海马超微结构及NMDAR活性的影响

目的：探讨白细胞介素1β(IL-1β)及白细胞介素1受体拮抗剂(IL-1ra)对癫痫的影响，揭示癫痫发作的免疫学机制。方法：实验于2003-10／2004-06在哈尔滨医科大学第二临床医学院实验中心完成，侧脑室注射生理盐水，IL-1β及IL-1ra 30min后戊四氮致痫观察大鼠行为，分别于致痫后2，8，24h处死大鼠，通过放射配基结合实验测定NMDA受体(NMDAR)活性，取海马CA3区电镜下观察超微结构的变化。结果：外源性IL-1β能够缩短癫痫发作的潜伏期，与生理盐水对照组相比差异有显著性意义(t=3．85，P&;lt;0．05)，对癫痫发作强度的影响与对照组相比差异无显著性意义，观察到明显的神经元变性坏死，大鼠脑内NMDAR活性在致痫后个时间点均显著增强；IL-1ra对发作潜伏期的影响及发作强度的影响与对照组相比差异无显著性意义，但可明显减轻戊四氮致痫所导致的神经元损害，致痫大鼠脑内NMDAR活性各时间与对照组相比明显减低。结论：IL-1β通过提高NMDAR活性促进癫痫发生及发展，加重癫痫所导致的神经元损伤的程度，IL-1ra可以通过抑制IL-1β的活性，减轻其上述作用。     

急性白血病患者血清白细胞介素-11及白细胞介素-1β测定分析

目的 探讨白细胞介素-11(IL-11)及白细胞介素-1β(IL-1β)在急性白血病(AL)诱导缓解过程中的变化及意义.方法 用酶联免疫吸附试验(ELISA)对24例健康体检者及45例初诊AL患者化疗前及获完全缓解(CR)后的血清IL-11及IL-1β含量进行动态观察,同时观察患者外周血白细胞和血小板计数的变化.结果 AL患者血清IL-1β含量[(84.63±16.74)ng/L]较正常对照组[(28.46±3.08)ng/L]高(t=-1.467,P=0.024),经诱导化疗获CR后又明显降至正常水平,且与外周血白细胞呈正相关(r=0.315,P<0.05),而IL-11[(23.64±2.04)μg/L]水平在初次诱导化疗前明显低于健康对照组[(63.52±18.72)μg/L,t=-1.795,P=0.039),获CR后明显升高,并接近正常水平,且与外周血血小板数呈正相关(r=0.813,P<0.05).结论 IL-11和IL-1β是判断急性白血病患者病情进展、疗效观察及预后的重要指标.     

白细胞介素1 β、白细胞介素1受体拮抗剂对癫痫大鼠行为、海马超微结构及NMDAR活性的影响

目的探讨白细胞介素1β(IL-1β)及白细胞介素1受体拮抗剂(IL-1ra)对癫痫的影响,揭示癫痫发作的免疫学机制.方法实验于2003-10/2004-06在哈尔滨医科大学第二临床医学院实验中心完成,侧脑室注射生理盐水,L-1β及IL-1ra 30 min后戊四氮致痫观察大鼠行为,分别于致痫后2,,24 h处死大鼠,通过放射配基结合实验测定NMDA受体(NMDAR)活性,取海马CA3区电镜下观察超微结构的变化.结果外源性IL-1β能够缩短癫痫发作的潜伏期,与生理盐水对照组相比差异有显著性意义(t=3.85,＜0.05),对癫痫发作强度的影响与对照组相比差异无显著性意义,观察到明显的神经元变性坏死,大鼠脑内NMDAR活性在致痫后个时间点均显著增强;IL-Ira对发作潜伏期的影响及发作强度的影响与对照组相比差异无显著性意义,但可明显减轻戊四氮致痫所导致的神经元损害,致痫大鼠脑内NMDAR活性各时间与对照组相比明显减低.结论IL-1 β通过提高NMDAR活性促进癫痫发生及发展,加重癫痫所导致的神经元损伤的程度,L-1ra可以通过抑制IL-1β的活性,减轻其上述作用.     

白细胞介素1β与癫痫发作相关性的Meta分析／

目的 系统评价白细胞介素1β（IL-1β）与癫痫发作的相关性。 方法 2012年5月－2013年10月检索PubMed数据库（1985年1月－2013年7月）、Medline数据库（1985年1月－2013年7月）、中国知网（1998年1月－2013年7月）和万方数据库（1996年1月－2013年7月）,并辅以谷歌学术搜索引擎进行手工检索。由两名研究者按照研究的纳入与排除标准进行病例对照研究的选择,对入选文献的质量参照“非随机对照临床试验质量评价标准与计分表”进行评价和计分,评估纳入研究的方法学质量并对有效的信息进行数据提取。然后采用RevMan 5.0统计软件进行Meta分析,以加权均数差（WMD）为效应指标。 结果 共纳入5个研究,包括82例癫痫发作的患者和471例正常对照。所纳入的研究未描述详细的抽样方法及其检测方法的特异性。Meta分析结果显示：癫痫发作72 h以内的患者与正常对照人群之间血浆IL-1β的浓度差异无统计学意义[WMD=0.04 pg/mL,95%CI（？0.07,0.16）pg/mL,P=0.46]。 结论 IL-1β可能没有直接参与癫痫的发作,而是通过与其他炎性因子之间的相互作用来实现。因此,需要进一步的研究来证明IL-1β在癫痫发作中的作用。     

抗γ-氨基丁酸B受体脑炎伴小细胞肺癌临床分析 及文献复习

目的：通过报道一例早期MRI阴性的伴小细胞肺癌抗γ-氨基丁酸B受体脑炎,探讨抗γ-氨基丁酸B(GABAB)受体脑炎的临床特点。方法：报道1例抗GABAB受体脑炎并文献复习。结果：患者以发作性意识障碍入院,表现为全身强直阵挛发作,逐渐出现定向力、近期记忆力、计算力障碍,及精神行为异常。颅脑MRI提示左侧海马异常信号（T2WI、FLAIR高信号）,脑脊液抗GABAB受体抗体阳性,PET-CT及淋巴结穿刺明确非小细胞肺癌并淋巴结转移。经免疫调节、放化疗等治疗后症状有所改善。笔者通过查阅、分析文献发现既往抗GABAB受体脑炎134例,多数呈癫痫起病,伴有精神行为异常以及意识改变。颅脑MRI常表现为单侧或双侧颞叶内侧、海马区异常信号,常伴小细胞肺癌,早期免疫治疗可缓解临床症状及改善预后。结论：抗GABAB受体脑炎有其独特的临床特点,免疫治疗可缓解临床症状及改善预后。     

白细胞介素-1基因多态性的研究进展

白细胞介素-1(interleukin-1，IL-l)是一个非常重要的前炎症细胞因子，其基因多态性与疾病的发生、发展密切相关，对IL-l基因多态性的研究有助于一些疾病的治疗。本文就IL-1基因多态性的研究进展作一综述。     

脓毒症大鼠海马白细胞介素-1β转化酶的表达及其意义

目的 探讨白细胞介素-1β转化酶在腹腔感染脓毒症致神经元损伤中的机制.方法 建立Wistar大鼠腹腔感染脓毒症模型,研究脓毒症后不同时间内海马组织ICE的活性,IL-1β含量变化及海马CA1区神经元计数的变化,同时观察用Ac-YVAD-FMK治疗后对上述指标的影响.结果 随着发生脓毒症时间的延长,脑海马组织中ICE活性和IL--1β含量显著升高(P＜0.05和P＜0.01),海马CA1区神经元计数显著降低(P＜0.05和P＜0.01).使用Ac-YVAD-FMK治疗后上述各指标的异常变化明显减轻,与模型组比差异具有统计学意义(P＜0.05和P＜0.01).结论 脓毒症后ICE主要通过炎症机制介导神经元的损伤,Ac-YVAD-FMK对脓毒症后神经元的损伤具有保护作用.     

Interleukin-1beta inhibits gamma-aminobutyric acid type A (GABA(A)) receptor current in cultured hippocampal neurons

Interleukin-1beta (IL-1beta), a polypeptide immune mediator, is induced within the central nervous system in response to a variety of pathological stimuli, including systemic infection, hypoxia, brain trauma, and seizure. IL-1beta action on the gamma-aminobutyric acid type A (GABA(A)) inhibitory neurotransmitter receptor was investigated in whole cell patch-clamped cultured hippocampal neurons. Application of IL-1beta at concentrations encountered in pathophysiological conditions (1-10 ng/ml; 59-590 pM) irreversibly decreased the peak magnitude of current elicited by 30 microM GABA. Current inhibition was IL-1beta concentration- and time-dependent and was prevented by a specific IL-1beta type I receptor antagonist. No significant changes in current kinetics or reversal potential were observed. The IL-1beta depression of GABA current was inhibited by high concentrations of nonspecific kinase inhibitors staurosporine (500 nM) and 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7; 50 microM), but not by a protein kinase C selective inhibitor calphostin C (5 microM). We conclude that IL-1beta inhibits GABA(A) receptor function in hippocampal neurons by the involvement of an unidentified kinase. This blockade of the GABA(A) inhibitory neurotransmitter receptor may underlie the central nervous system hyperexcitability seen in many pathophysiological conditions.     

慢性乙型肝炎患者白细胞介素1β及白细胞介素1受体拮抗剂基因多态性分析

目的探讨白细胞介素1β(IL-1β)基因启动子区域-511C/T和白细胞介素1受体拮抗剂(IL-1RN)基因在慢性乙型肝炎及正常人群中的多态性,初步分析其基因型与慢性乙型肝炎的相关性.方法对190例慢性乙型肝炎患者和249例正常人IL-1β、IL-1RN基因进行PCR扩增,其中IL-1β基因用AvaI限制性内切酶对PCR产物进行消化,然后经琼脂糖凝胶电泳分别对IL-1β、IL-1 RN基因多态性进行分析.结果慢性乙型肝炎患者IL-1RN 1/2基因型和IL-1RN2等位基因频率均明显低于正常对照组(P<0.025,P<0.05).在乙型肝炎病毒(HBV) DNA水平不同的2组慢性乙型肝炎患者中,IL-1β基因启动子-511位点CC型分布差异有显著性(χ2=4.77,P<0.05).结论慢性乙型肝炎与IL-1β、IL-1RN基因的多态性有关,其中IL-1RN2等位基因可能对乙型肝炎病毒感染有保护作用,而IL-1β基因中的CC型可能对感染后HBV DNA的复制有抑制作用.     

Interleukin-1-beta gene, but not the interleukin-1 receptor antagonist gene, is associated with Graves' disease

Interleukin-1 (IL-1) is considered to be involved in the pathogenesis of Graves' disease. The aim of this study was to test whether the IL-1-beta gene promoter region and exon 5 and IL-1 receptor antagonist (IL-1Ra) gene intron 2 polymorphisms could be useful genetic markers for susceptibility to Graves' disease. A normal control group of 163 healthy people and another group of 95 patients with Graves' disease were examined. Polymerase chain reaction (PCR) was used to analyze the variable number of tandem repeats (VNTRs) at intron 2 of the IL-1Ra gene for the polymorphism. PCR-based restriction analysis was done for the IL-1-beta gene polymorphisms of the promoter region and exon 5 using endonucleases AvaI and TaqI, respectively. We found significantly increased frequencies of the C/C homozygous genotype (chi(2) test, P=0.038; odds ratio (OR)=2.558, 95% confidence interval (CI)=1.205-5.430) and the C allele (chi(2) test, P=0.011; OR=1.589, 95% CI=1.094-2.309) in the IL-1-beta gene promoter (-511 C/T polymorphism) in Graves' disease patients compared to normal controls. There were no significant differences in polymorphisms of IL-1-beta gene exon 5 and IL-1Ra gene intron 2 between the patient and normal control groups. A subgroup analysis also demonstrated no association between the severity of the disease and any polymorphism of IL-1-related genes. We suggest that the IL-1-beta gene promoter polymorphism can be used as a genetic marker for susceptibility to Graves' disease. It is worthwhile to study the cytokine genes further because of the association between cytokines and Graves' disease.     

Live Borrelia burgdorferi preferentially activate interleukin-1 beta gene expression and protein synthesis over the interleukin-1 receptor antagonist.

Lyme arthritis is one of the few forms of chronic arthritis in which the cause is known with certainty. Because cytokines are thought to contribute to the pathogenesis of chronic arthritis, we investigated the effect of the Lyme disease spirochete, Borrelia burgdorferi, on the gene expression and synthesis of IL-1 beta and the IL-1 receptor antagonist (IL-1ra) in human peripheral blood mononuclear cells. Live B. burgdorferi induced fivefold more IL-1 beta than IL-1 alpha and sevenfold more IL-1 beta than IL-1ra; LPS or sonicated B. burgdorferi induced similar amounts of all three cytokines. This preferential induction of IL-1 beta was most dramatic in response to a low passage, virulent preparation of B. burgdorferi vs. three high passage avirulent strains. No difference in induction of IL-1ra was seen between these strains. The marked induction of IL-1 beta was partially diminished by heat-treatment and abrogated by sonication; IL-1ra was not affected. This suggested that a membrane component(s) accounted for the preferential induction of IL-1 beta. However, recombinant outer surface protein beta induced little IL-1 beta. By 4 h after stimulation, B. burgdorferi induced sixfold more IL-1 beta protein than LPS. In contrast to LPS-induced IL-1 beta mRNA which reached maximal accumulation after 3 h, B. burgdorferi-induced IL-1 beta mRNA showed biphasic elevations at 3 and 18 h. B. burgdorferi-induced IL-1ra mRNA peaked at 12 h, whereas LPS-induced IL-1ra mRNA peaked at 9 h. IL-1 beta synthesis increased in response to increasing numbers of spirochetes, whereas IL-1ra synthesis did not. The preferential induction by B. burgdorferi of IL-1 beta over IL-1ra is an example of excess agonist over antagonist synthesis induced by a microbial pathogen, and may contribute to the destructive lesion of Lyme arthritis.     

Interleukin-1 receptor antagonist in normal and psoriatic epidermis.

The objective of these studies was to characterize the IL-1 inhibitory activity present in normal and psoriatic epidermis from clinically stable lesions. Fractionation of normal epidermal cytosol on a molecular sizing column failed to reveal the presence of IL-1 inhibitory bioactivity. However, specific ELISAs indicated that both the IL-1 receptor antagonist (IL-1ra) and IL-1 alpha were present in overlapping peaks. Further fractionation of the normal epidermal cytosol by anion exchange chromatography separated these two molecules, revealing the IL-1 inhibitory bioactivity of the IL-1ra molecule. Similar studies on psoriatic epidermal cytosol indicated the presence of IL-1 inhibitory bioactivity and IL-1ra protein. The IL-1 inhibitory bioactivity of both normal and psoriatic cytosol was neutralized by a mAb specific for IL-1ra. The ratio of IL-1ra to IL-1 alpha proteins was significantly increased in involved psoriatic skin compared with normal skin. By Western blot analysis this IL-1ra was approximately 20 kD, slightly larger than monocyte-derived IL-1ra and equivalent to an intracellular variant of IL-1ra expressed by keratinocytes. Polymerase chain reaction indicated the presence of mRNA for both forms of IL-1ra in normal epidermis, with both forms increased in psoriatic-involved skin. Immunofluorescence studies revealed the IL-1ra protein to be concentrated in the stratum granulosum of normal skin and in the basal-midbasal layers of psoriatic epidermis. These results suggest that the balance between intracellular IL-1ra and IL-1 alpha may be an important influence on keratinocyte growth and/or differentiation, as well as on the inflammatory potential of IL-1 in injured skin.     

Polymorphism of interleukin-1 receptor antagonist gene and obesity

Background: Cytokines appear to be major regulators of adipose tissue metabolism. Interleukin-1 receptor antagonist (IL-1ra) serum concentrations are increased in human obesity, and are under strong genetic control. We tested the hypothesis that the IL-1ra gene might be a candidate for obesity. Methods: We investigated the frequency of a penta-allelic 86-bp tandem repeat (VNTR) in the intron 2 of IL-1ra gene in 52 lean (body mass index (BMI) <25 kg/m²), 133 overweight (BMI 25–29.9 kg/m²) and 76 obese (BMI ≥30.0 kg/m²) otherwise healthy Korean women. Total fat mass and percent body fat were determined by dual-energy X-ray absorptiometry. Genomic DNA was extracted and used for polymerase chain reaction-based genotyping of IL-1ra. Results: Carriers of the allele 2 did not show a significant difference in physical and clinical characteristics. The genotypic, or allelic distribution did not differ markedly between the three groups. The relative risk of being obese in comparison with lean group tended to be higher in allele 2 carriers, but not significantly. Conclusions: We found no relationship between the IL-1ra polymorphism and BMI in Korean women.     

Interleukin-1 receptor antagonist as therapy for inflammatory disorders

IL-1 is a pivotal mediator of the immune response and has been implicated in inflammatory and infectious diseases. As a consequence, the administration of IL-1 receptor antagonist (IL-1ra), a recombinantly synthesised endogenous inhibitor of IL-1, has appeal as a therapeutic strategy in these conditions. To date, the largest clinical experiences with IL-1ra have been in the setting of sepsis and rheumatoid arthritis (RA). Like other anti-inflammatory agents that target a specific mediator, IL-1ra was found to lack efficacy when given in conjunction with standard therapy in patients with sepsis and septic shock. In contrast, recent studies enrolling patients with RA suggest that IL-1ra significantly ameliorates disease activity and retards joint destruction. Whether the respective lack of efficacy and success of IL-1ra in these two diseases is a result of differences in the pathologic processes involved, or reflects the nature in which the clinical studies were conducted, is unclear. Further, the effectiveness of IL-1ra compared to other anticytokine and conventional treatments in RA remains to be clarified. Nonetheless, the recent finding that IL-1ra has the ability to favourably influence a chronic inflammatory disease supports the hypothesis that inhibition of a single mediator of the immune response may have clinical impact.     

The inhibitory activity of human interleukin-1 receptor antagonist is enhanced by type II interleukin-1 soluble receptor and hindered by type I interleukin-1 soluble receptor.

Interleukin-1 (IL-1) is a major proinflammatory cytokine produced by monocytes/macrophages. At the inflammatory site, IL-1 is a potent inducer of the production of prostaglandin E2 (PGE2) and metalloproteinases on fibroblast-like cells, thus triggering tissue damage. The biological activity of IL-1 is counterbalanced by two types of inhibitors: the IL-1 receptor antagonist (IL-1Ra) which competitively binds IL-1 receptor without inducing signal transduction; and IL-1 soluble receptors (IL-1sR) which bind IL-1 and diminish the free concentration of soluble cytokine, thus hampering its binding to the cell surface receptor. Since IL-1sR can also bind IL-1Ra, we studied the simultaneous effects of both inhibitors on the production of interstitial collagenase (C'ase) and PGE2 by human dermal fibroblasts and synovial cells stimulated by either IL-1 alpha or IL-1 beta. IL-1Ra inhibited fibroblast and synovial cell stimulation by approximately 90%, with the exception of C'ase production by synovial cells which was inhibited by approximately 55%. Type I IL-1sR (IL-1sRI) preferentially inhibited IL-1 alpha, whereas type II IL-1sR (IL-1sRII) mainly inhibited IL-1 beta. When IL-1Ra was used simultaneously with IL-1sRI, the final inhibition was lower than that of either of the inhibitors. The simultaneous presence of IL-1Ra and IL-1sRII abolished the IL-1-induced production of PGE2 and C'ase on both dermal fibroblasts and synovial cells, demonstrating that concurrently these two inhibitors are able to abolish most of the inflammatory response. To our knowledge, this is the first example of two types of inhibitors that abolish each other's effects, one of which acts at the receptor level and the other at the ligand level, thus leaving ligand activity unimpaired.